Chronic pain following surgical incisions is a major clinical problem. As used herein, the term “chronic pain” refers to pain lasting at least three (3) months and typically at least six (6) months, e.g., after surgery, injury or a disease. Currently available therapeutics given for acute post-surgical pain (opiates and non-steroidal anti-inflammatory drugs, i.e., NSAIDs) do not always prevent the transition to chronic post-surgical pain. Furthermore, opiates and NSAIDs can be habit forming and/or patients develop tolerance to these drugs, thereby requiring increased dosage. Moreover, because these drugs are typically administered orally, many patients suffer adverse gastrointestinal discomfort.
Therefore, there is a need to develop a composition that can treat pain without some of the disadvantages exhibited by opiates and NSAIDs. The aim is to establish AMPK activation as a mechanism for the alleviation of post-surgical, and possibly other persistent pain states and to utilize novel therapeutics that employ this mechanism of action of use in humans. Dysregulated protein translation regulation pathways that underlie persistent pain states can be negatively regulated by activation of endogenous signaling factor AMPK.
The present invention features a novel therapeutic based on activation of adenosine monophosphate protein kinase (AMPK) to treat both acute post-surgical pain and prevent the transition to chronic pain. AMPK activators that possess different mechanisms of AMPK activation to demonstrate a shared endpoint, such as metformin and resveratrol, are used to accomplish this. Co-treatment with metformin and resveratrol doses at the time of incision block acute hypersensitivity and hyperalgesic priming suggesting potential super-additive effects of combined AMPK activator use.